Experiment 38 involves screening the
full NCI library of 316,179 compounds against the newly-discovered allosteric binding site on HIV-1 integrase. This new
allosteric binding site was discovered by Professor John J. Deadman's group, and it was described in "Structural basis for a new
mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design," by D.I. Rhodes, T.S. Peat,
J.J. Deadman, et al., published in the journal Antiviral Chemistry and Chemotherapy, 21: 155-168 (2011). The new
crystal structure from this paper that contains the atomically-detailed, 3-D data on this new allosteric site is called "3NF6.pdb". We are screening
compounds against this allosteric site to try to discover new, larger, more potent allosteric inhibitors of HIV-1 integrase. It is hoped that these new
allosteric inhibitors of integrase will be effective at disabling the current drug-resistant mutant superbugs of HIV integrase. For more information
about this new allosteric site, see Volume 10 of the FightAIDS@Home newsletter (pages 7-8) or our recent World AIDS Day webinar (both are linked at the top of the homepage for this site).

This experiment involves faah26,179 - faah26,810.
These calculations began 12/06/2011 and ended 12/22/2011.

Experiment 37: 100% Completed

Experiment 37 involves screening the newly-updated version of the
Asinex library of 360,00 compounds. 507,000 different models are used to represent these 360,000 compounds (due to the need to represent
different protonation states and different tautomers that some of these compounds can form in solution). These compounds are being
screened against the active site and the "eye site" of 6 different crystal structures of HIV protease. When the flaps have a
semi-open conformation, then we can target both the "eye site" and the floor of the active site. But when the flaps have a closed conformation,
the "eye site" is no longer accessible (which means that we will only target the traditional active site, which is where the current HIV protease drugs bind).

The 1st target is the crystal structure of the wild type HIV protease with 5-nitroindole bound in the
eye site. This new crystal structure from Prof. C. David Stout's lab was presented in the Supporting
Information for our recent article in
Chemical Biology and Drug Design, vol. 75: 257-268 (March 2010). Since this crystallographic structure has semi-open flaps,
we are screening these compounds against both the eye site and the active site of this target.

The 2nd target is the semi-open crystal structure of wild type HIV-1b protease from 1HHP.pdb. This crystal structure has been used in previous virtual screens that were performed by Prof. Heather Carlson's group, in which they did find
a novel inhibitor of HIV protease activity. Thus, this particular crystal structure has already been proven to be useful for virtual screens that target the "eye site." The idea of targeting this eye site was first proposed by Prof. Heather Carlson's group. But in this experiment, we are screening different compounds against
this crystal structure than the compounds that were used in previous screens against 1HHP.pdb.

The 3rd target has only been used in one previous FightAIDS@Home experiment (i.e., Experiment 35). It is a brand new crystal structure from Assoc. Prof. C. David Stout's lab
of the
chimeric "FIV 6s98S" protease, which was developed by our collaborators Ying-Chuan Lin, Prof. Bruce E. Torbett, and Prof. John H. Elder, and which has a closed conformation of the flaps. A paper on this
new crystal structure of FIV 6s98S protease was recently accepted for publication in Acta Crystallographica and can be found at the above link. This protease enzyme is "chimeric," because it contains 5 residues
from HIV protease that were substituted into the corresponding positions in FIV protease. The 6th residue was also substituted from HIV protease, but it changed into
a different residue during serial passage experiments (i.e., during directed evolution studies).
This 6s98S FIV protease has HIV-like drug sensitivity profiles and is a new model system for multi-drug-resistant HIV protease.

The 4th target is the crystal structure of wild type HIV-1b protease bound to the drug darunavir. This crystal structure from
2IEN.pdb has a closed conformation of the flaps. Whenever we target a crystal structure of HIV protease that has a compound bound to it, we delete that ligand before we prepare the model of the target for these docking studies (so that a new compound might be able to bind in its place).

The 6th target is the crystal structure of the V82F/I84V multi-drug-resistant mutant (or "superbug") of HIV protease from 1MSN.pdb, which has closed flaps. The model of this target has one protonated aspartic acid 25 (i.e., one of the two catalytic residues), which should cause us to fish out slightly different types of ligands.

The 7th target is another version of the semi-open crystal structure of wild type HIV-1b protease from 1HHP.pdb. That is, this is the same molecule as the 2nd target in this experiment,
but this time the model has one protonated aspartic acid 25.

This experiment involves faah22,630 - faah26,178.
These calculations began 5/12/2011 and ended 12/15/2011 (except for 3 batches, which were finished on 2/07/2012).

Experiment 36: 100% Completed

Experiment 36 involves screening the
full NCI library of ~ 316,000 compounds against the two allosteric sites on the surface of HIV protease.
This experiment is similar to Exp. 31, but a different library of compounds is being screened, and in this experiment
we are only docking compounds against the two allosteric-fragment-bound crystal structures from
our recent article in
Chemical Biology and Drug Design, vol. 75: 257-268 (March 2010).
In addition, in this experiment we are investigating four slightly different docking protocols, to both
advance the methods we use for drug discovery and to increase our probability of finding new "hits" against
HIV protease. Since two different allosteric-fragment-induced structures are being used with four slightly
different protocols, this experiment is composed of 8 parts, as follows:
1a) The crystal structure bound to allosteric fragment "1f1" is being screened using an "expanded grid box" that
includes the 1f1 allosteric site, the 4d9 allosteric site (in the non-induced conformation = a decoy site), and several other decoy sites.
The docking calculations will end according to the number of generations each compound explores in the genetic algorithm (that is,
all 316,000 compounds will experience the same number of generations as they explore the target).
1b) The crystal structure bound to allosteric fragment "4d9" is being screened using an "expanded grid box" that
includes the 4d9 allosteric site, the 1f1 allosteric site (in the non-induced conformation = a decoy site), and several other decoy sites.
The docking calculations will end according to the number of generations each compound explores in the genetic algorithm (that is,
all 316,000 ligands will experience the same number of generations as they explore the target).

2a) The crystal structure bound to allosteric fragment "1f1" is being screened using an "expanded grid box" that
includes the 1f1 allosteric site, the 4d9 allosteric site (in the non-induced conformation), and several other decoy sites.
The docking calculations will end according to the number of energy evaluations each ligand explores in the genetic algorithm (that is,
all 316,000 compounds will experience the same number of energy evaluations as they explore the target).
2b) The crystal structure bound to allosteric fragment "4d9" is being screened using an "expanded grid box" that
includes the 4d9 allosteric site, the 1f1 allosteric site (in the non-induced conformation), and several other decoy sites.
The docking calculations will end according to the number of energy evaluations each compound explores in the genetic algorithm (that is,
all 316,000 ligands will experience the same number of energy evaluations as they explore the target).

3a) The crystal structure bound to allosteric fragment "1f1" is being screened using a "focused grid box" that only
includes the 1f1 allosteric site (that is, no decoy sites were included in the grid box that the compounds are allowed to explore).
The docking calculations will end according to the number of energy evaluations each ligand explores in the genetic algorithm (that is,
all 316,000 compounds will experience the same number of energy evaluations as they explore the target).
3b) The crystal structure bound to allosteric fragment "4d9" is being screened using a "focused grid box" that only
includes the 4d9 allosteric site (that is, no decoy sites were included in the grid box that the compounds are allowed to explore).
The docking calculations will end according to the number of energy evaluations each compound explores in the genetic algorithm (that is,
all 316,000 ligands will experience the same number of energy evaluations as they explore the target).

4a) The crystal structure bound to allosteric fragment "1f1" is being screened using a "focused grid box" that only
includes the 1f1 allosteric site (that is, no decoy sites were included in the grid box that the compounds are allowed to explore).
The docking calculations will end according to the number of generations each ligand explores in the genetic algorithm (that is,
all 316,000 compounds will experience the same number of generations as they explore the target).
4b) The crystal structure bound to allosteric fragment "4d9" is being screened using a "focused grid box" that only
includes the 4d9 allosteric site (that is, no decoy sites were included in the grid box that the compounds are allowed to explore).
The docking calculations will end according to the number of generations each ligand explores in the genetic algorithm (that is,
all 316,000 ligands will experience the same number of generations as they explore the target).

This experiment involves faah20,093 - faah22,620.
These calculations began 4/16/2011 and ended 7/01/2011.

Experiment 35: 100% Completed

Experiment 35 involves screening the
full NCI library of ~ 316,000 compounds against the active site of 8 different versions of HIV protease. Thus,
this experiment is similar to Exp. 32, but a different library of compounds is being screened, and
one new target has been added. All but two of these target conformations were generated by
Dr. Alex L. Perryman's Molecular Dynamics (MD) simulations of 5 different variants of HIV protease. These
8 targets include 2 snapshots of the V82F/I84V mutant from ALP's 2004 paper in Protein Science. These
2 snapshots of a multi-drug-resistant "superbug" have semi-open conformations of the flaps, which
makes these models good targets for the "eye site" that is located between the tip of a semi-open flap and the
top of the wall of the active site. The 3rd target is the equilibration MD (EqMD) output for 1HSI.pdb,
which is a semi-open conformation of HIV-2 protease. HIV-2 is the group of strains of HIV that are
most common in Africa. We'll be targeting the "eye site" of 1HSI, as well. The 4th target is the
EqMD output from 1MSN.pdb, which was created using a different crystal structure of the V82F/I84V superbug. This model
has a closed conformation of the flaps, which means that we'll be targeting the floor of the active site.
The 5th target also has a closed conformation of the flaps, but this EqMD output is from 2R5P.pdb, which
is the wild type HIV-1c protease. HIV-1c is the group of strains of HIV that are most commonly found in Asia.
The 6th target has semi-open flaps, and it is the EqMD output from 1TW7.pdb, which is a superbug
with the mutations L10I/D25N/M36V/M46L/I54V/I62V/L63P/A71V/V82A/I84V/L90M. We'll be targeting the
eye site of this superbug, too.

The 7th target is a crystal structure of the wild type HIV protease with 5-nitroindole bound in the
eye site. This new crystal structure from Prof. C. David Stout's lab was presented in the Supporting
Information for our recent article in
Chemical Biology and Drug Design, vol. 75: 257-268 (March 2010). This new
research article of ours was recently discussed in a
press release on Science Daily and in a
news story on KPBS-FM. This paper was recently listed as one of the "most read papers" from Chemical Biology and Drug Design in 2010!
I deleted the 5-nitroindole fragment from this structure before generating the AutoDock input file for this target.
We'll be screening new fragments against this crystal structure's eye site, as well.

The 8th target has never been used on FightAIDS@Home before. It is a brand new crystal structure from Assoc. Prof. C. David Stout's lab
of the
chimeric "FIV 6s98S" protease, which was developed by our collaborators Ying-Chuan Lin, Prof. Bruce E. Torbett, and Prof. John H. Elder. A paper on this
new crystal structure of FIV 6s98S protease is currently being peer-reviewed. This protease enzyme is "chimeric," because it contains 5 residues
from HIV protease that were substituted into the corresponding positions in FIV protease. The 6th residue was also substituted from HIV protease, but it changed into
a different residue during serial passage experiments (i.e., during directed evolution studies performed with the presence of different HIV protease drugs).
This 6s98S FIV protease has HIV-like drug sensitivity profiles and is a new model system for multi-drug-resistant HIV protease.

This experiment involves faah17,565 - faah20,092.
These calculations began 11/26/2010 and ended 4/25/2011.

Experiment 34: 100% Completed

Experiment 34 is our second FightAIDS@Home experiment that targets
the HIV integrase system. See the description and the link listed under Experiment 33.

Experiment 34 involves screening the "full National Cancer Institute's (NCI) library" of over 315,000 different compounds against our new dynamic models
of the wild type, the G140S/Q148H drug-resistant mutant, and the E92Q/N155H drug-resistant mutant of HIV-1 integrase.
We are trying to discover compounds that can bind to and inhibit the active site of the wild type and these two drug-resistant mutants. Since
these models all have two magnesium ions in the active site, we are searching for compounds that can inhibit HIV integrase's "strand transfer
reaction," which is what the fairly new drug raltegravir (Isentress) does.

We are screening the NCI library of compounds against 4 different snapshots (that is, conformations or 3-D shapes) of HIV integrase:
a) the conformation of wild type HIV integrase against which raltegravir docked the best (in the results published in our paper in the Journal of Molecular Biology, March 26, 2010),
b) the snapshot of the G140S/Q148H drug-resistant mutant against which raltegravir docked the best in our previous studies,
c) the most representative (that is, the most frequently observed) conformation of the E92Q/N155H drug-resistant mutant (according to the results of the QR Factorization method in VMD), and
d) the 2nd most representative conformation of the E92Q/N155H drug-resistant mutant of HIV integrase's catalytic core domain.

The best compounds from this virtual screen will be assessed in test tubes, in "strand transfer" assays being developed by our collaborator
Dr. Ying-Chuan Lin in Prof. John Elder's lab at TSRI.

This experiment involves faah16,199 - faah17,462.
An extension to this experiment in which the NCI Diversity Set II library of
compounds is being screened against these targets involves faah17,463 - faah17,466.
A second extension to this experiment in which the "high pH" version of the full NCI library of compounds is being
screened against these targets involves faah17,473 - faah17,564.
These calculations began 10/11/2010 and ended 1/16/2011.

Experiment 33 involves screening the "Asinex library" of over 360,000 different fragments and slightly
larger compounds against our new dynamic models of the E92Q/N155H drug-resistant mutant of HIV-1 integrase.
We are trying to identify compounds that can attach to brand new binding sites on this
mutant. Thus, we are both searching for new types of inhibitors and for new, non-active site regions to which inhibitors can bind.
We are screening these compounds against 6 different snapshots of this mutant that had the
most open conformations of the "140s loop" near the active site. This loop is known to be critical to the catalytic function
of integrase. This 140s loop is located in the top, left corner of the image at the bottom of this page. Since the 140s loop
likely has a closed conformation during catalysis, we are searching for fragments that can stabilize the open, likely
inactive conformations of the 140s loop. In other words, we are searching for fragments that might act as
allosteric inhibitors (flexibility wedges that alter the shapes and motions sampled by this very flexible loop).
The best compounds from this virtual screen will be assessed in test tubes, in "3' processing" assays performed by our collaborator
Dr. Ying-Chuan Lin in Prof. John Elder's lab at TSRI.

This experiment involves faah13,985 - faah16,198.
An extension to this experiment in which the NCI Diversity Set II library of
compounds is being screened against these targets involves faah17,467 - faah17,472.
These calculations began 6/03/2010 and ended 12/01/2010.

Jan. 2011 update: 10 of the top-ranked compounds were purchased and are currently be tested by our collaborators at TSRI.

TARGET: Y3/Mg Site of IN

AD Exp. 33

AD Exp. 33 ext. 1

Receptor Structure

Asinex

NCI Div. II

MD Snapshot 1-04080 of PDB 1QS4

13985-14353

17467

MD Snapshot 2-00020 of PDB 1QS4

14354-14722

17468

MD Snapshot 2-00260 of PDB 1QS4

14723-15091

17469

MD Snapshot 3-02740 of PDB 1QS4

15092-15460

17470

MD Snapshot 3-07720 of PDB 1QS4

15461-15829

17471

MD Snapshot 3-07910 of PDB 1QS4

15830-16198

17472

COMPLETION

100%

100%

Experiment 32: 100% Completed

Experiment 32 involves screening the
Otava library of approximately 335,000 "building blocks" (i.e., fragments) against the
active site of 7 different versions of HIV protease. All but one of these target conformations were generated by
Dr. Alex L. Perryman's Molecular Dynamics (MD) simulations of 5 different variants of HIV protease. These
7 targets include 2 snapshots of the V82F/I84V mutant from ALP's 2004 paper in Protein Science. These
2 snapshots of a multi-drug-resistant "superbug" have semi-open conformations of the flaps, which
makes these models good targets for the "eye site" that is located between the tip of a semi-open flap and the
top of the wall of the active site. The 3rd target is the equilibration MD (EqMD) output for 1HSI.pdb,
which is a semi-open conformation of HIV-2 protease. HIV-2 is the group of strains of HIV that are
most common in Africa. We'll be targeting the "eye site" of 1HSI, as well. The 4th target is the
EqMD output from 1MSN.pdb, which was created using a different crystal structure of the V82F/I84V superbug. This model
has a closed conformation of the flaps, which means that we'll be targeting the floor of the active site.
The 5th target also has a closed conformation of the flaps, but this EqMD output is from 2R5P.pdb, which
is the wild type HIV-1c protease. HIV-1c is the group of strains of HIV that are most commonly found in Asia.
The 6th target has semi-open flaps, and it is the EqMD output from 1TW7.pdb, which is a superbug
with the mutations L10I/D25N/M36V/M46L/I54V/I62V/L63P/A71V/V82A/I84V/L90M. We'll be targeting the
eye site of this superbug, too.

The Protein Data Bank is located at
http://www.rcsb.org/pdb/home/home.do. You can search the PDB
using the 4 character codes listed above (i.e., before the .pdb suffix) to learn more about each of these
targets.
This experiment involves faah11,647 - faah13,984.
These calculations began 4/12/2010, they were put "on hold" for a while, and they finished 3/06/2011.

Experiment 31: 100% Completed

Experiment 31 involves screening the
Otava library of approximately 335,000 "building blocks" against the
"exo sites" on the side surfaces of HIV protease (i.e., the allosteric sites).
This experiment will dock these fragments against the exo sites of 8 different
targets, which include 5 carefully-selected snapshots from previous Molecular Dynamics
simulations of the V82F/I84V multi-drug-resistant mutant "super bug." The other targets
correspond to the two new fragment-bound crystal structures of HIV protease that
were produced by our collaborator, Prof. C. David Stout at TSRI. We are targeting
both sides of one of these two new targets, which is why we have "8 different targets."
These two new structures from Prof. Stout were also targeted in Experiments 25-28 and 30.
This experiment involves faah8972 - faah11,646.
These calculations began 12/07/2009 and ended 4/18/2010.

Experiment 30: 100% Completed

Like Experiment 29, Experiment 30 also uses
the "Asinex" library of over 360,000 different compounds in a virtual screen against HIV protease. But in this experiment,
the Asinex compounds are being docked against the allosteric inhibitor site (that is, the
"exo site" on the sides of HIV protease). In addition, this experiment targets
two new fragment-bound crystal structures of protease that were produced by our collaborator, Prof. C. David Stout at TSRI. These
two new structures from Prof. Stout were also targeted in Experiments 25-28.
This experiment involves faah8234 - faah8971.
These calculations began 10/05/2009 and ended 12/07/2009.

Update May, 2012: from the initial analysis of the results against the "1F1" allosteric site on the outside/top of the flaps, 10 fragments were purchased (using some of the funds that
IBM's "Watson" won on Jeopardy! and which the IBM International Foundation donated to the FightAIDS@Home project). These 10 fragments were analyzed by Max Chang in Prof. Bruce Torbett's lab in
"DSF" assays (differential scanning fluorimetry), which measure the thermal stability (melting temperature) of HIV protease in solution.
5 of these 10 fragments caused a significant shift in HIV protease stability in solution, which indicates that these
compounds are able to bind to HIV protease. These 5 fragments are now being investigated in further tests performed by the Finn lab, the Elder lab, and the
Stout lab.

Experiment 29: 100% Completed

This experiment involves docking a huge library of compounds against the
active site of six of our new models of HIV protease (which are a subset of the targets being used in Experiments 25-27). These six targets are the outputs of the equilibration phase of six different Molecular Dynamics simulations
(hence the "mdEq" part of the work units' names). The six different types of HIV protease that we are docking compounds against in Exp. 29
include the "Model6Xapo," which is a drug-resistant "super bug" with 6 different mutations. Our collaborator, Prof. Dave Stout, figured out the
structure of this 6X mutant. The "apo" part of the name indicates that this mutant protease molecule did not have a substrate or drug present when
its structure was solved. This Model6Xapo has semi-open flaps (that is, the two double-arrows that point towards the center of the molecule
and form a roof over the active site have opened up). We've been working with the IBM members of the FAAH team to update the graphics on your screen-savers. We've sent
them new graphics to use, and they've already started testing them. Soon, you will be able to see exactly what we mean when we say "semi-open flaps."
Another new model that is being targeted in Exp. 29 is the wild type HIV protease from 1HHP.pdb. We consider this model to be interesting, because the flaps were fairly open, but then they
closed again. But this time, they closed down in the opposite arrangement/they "switched handedness" (that is, the flap that is normally in the front is now in the back). Having this different
conformation of the flaps might allow us to fish out new types of interesting compounds for subsequent examination in the "test tube."
We included models of a multi-drug-resistant "super bug" with mutations at V82F/I84V and another "super bug" with
mutations at I62V/V82A/I84V/L90M.
We are targeting a model of the protease molecule from "HIV-1c," as well. HIV-1c is the subtype, or group of strains,
that is most commonly found in Asia. We are also targeting a model of "HIV-2" protease with semi-open flaps. HIV2 is the group of strains that
are most commonly found in Africa. The current anti-AIDS drugs were developed and optimized against "HIV-1b," which is the subtype most commonly found in
Europe and the USA. But some of these anti-HIV protease drugs do not work as well against even the wild type strains that are found in other regions (let alone their "super bugs").
Since we are not controlled by the desire to make profit, we are devoting some of our research efforts to the groups of HIV strains that affect the often-neglected patients in
Africa and Asia. In addition, studying these versions of HIV protease can also help us learn how to defeat the "super bugs" we find here in the USA.
This experiment is the first one in which we are using the "Asinex" library of over 360,000 different compounds in our virtual screens against HIV protease.
This experiment involves faah6022 - faah8233.
These calculations began 4/23/2009 and ended 10/20/2009.

Experiment 28: 100% Completed

This experiment utilizes the same set of brand new crystal structures
and new models of HIV protease that are being used in Experiments 25-27. See the description of Experiment 25 for the details about
these new targets. In experiment 28, we are AutoDocking these compounds against the active site of different variants of HIV protease.

This experiment incorporates a library of ligands that we just started using: the ChemBridge building blocks library. The library of "building blocks"
from ChemBridge contains many small fragments that were derived from larger compounds. Using these
small fragments, or building blocks, should help us cover a larger amount of structural diversity (i.e., of "chemical space") within
each experiment. Thus, this library should help us find new hits in a more efficient way.
This experiment involves faah5710-6021.
These calculations began 4/05/2009 and finished 4/24/2009.

Feb. 2011 update: 10 of the top-ranked fragments were purchased and are currently being tested by our collaborators at TSRI.
Preliminary data indicate that 2 of these 10 fragments are able to inhibit HIV protease, according to the
standard FRET-based activity assay. More testing needs to be done before we can publish these results, but thus far it appears that
we discovered 2 completely novel "hits" against the active site/"eye site" in the results of Experiment 28.

Extension to Experiment 28
736 compounds from the "ZINC" server
that are somewhat similar to these 2 active fragments (discussed above) were hand-picked by Dr. Alex L. Perryman.
These 736 compounds generate a "focused library" that we are screening against the active site and the
"eye site" of a panel of 9 different variants of HIV protease. Since these 736 compounds are larger than the
two active fragments discovered in Experiment 28, this extension of the experiment is searching for more potent compounds
that are also able to target both the "eye site" and the floor of the active site.
This extension involves faah22,621 - faah22,629.
These calculations began 6/01/2011 and ended 6/04/2011.

Experiment 27: 100% Completed

This experiment utilizes the same set of brand new crystal structures
and new models of HIV protease that are being used in Experiments 25 and 26. See the description of Experiment 25 for the details about
these new targets. In experiment 27, we are targeting the exo site on the sides of HIV protease.

This experiment incorporates a library of ligands that we have never used before. We recently downloaded
and reformatted the "ChemBridge building blocks library" of ~ 12,000 models of compounds from
"ZINC," (which stands for Zinc Is Not Commercial). See the paragraph below for a few details about
ZINC. The library of "building blocks" from ChemBridge contains many small fragments that were derived from larger compounds. Using these
small fragments, or building blocks, should help us cover a larger amount of structural diversity (i.e., of "chemical space") within
each experiment. Thus, this library should help us find new hits in a more efficient way.
This experiment involves faah5398 - faah5709.
These calculations began 3/26/2009 and finished 4/09/2009.

Similar to Experiment 25, this experiment also involves screening
the NCI's "DTP library of moderately active compounds" against several brand new structures and new models of HIV protease. But in
this experiment, we are docking the potential inhibitors against the active site, instead of the exo site. See the description
of Experiment 25 for the details regarding the new structures and models that we are targeting.
This experiment involves faah5320 - faah5397.
These calculations began 3/16/2009 and ended on 3/31/2009.

Experiment 25: 100% Completed

This experiment involves screening the NCI's "DTP library of moderately
active compounds" against the exo site of several brand new structures and new models of HIV-1b protease. (See the description of "Experiment 21" for more details about this
DTP library.) This experiment targets the potential allosteric inhibitor site (i.e., the "exo site") on the sides of HIV protease. The
new structures utilized in this experiment are based on brand new, currently unpublished x-ray crystallographic structures from our collaborator,
Prof. David Stout.

The new models of HIV protease that are also included in this experiment were
harvested from Molecular Dynamics simulations recently performed by Dr. Alex L. Perryman. We harvested the equilibrated structures from the beginnings of our
new MD simulations on several different multi-drug-resistant mutants of HIV-1b protease (i.e., several different "super bugs" against which the current drugs no longer work well.)
We also included models of HIV-1c protease ("1c" is the HIV subtype, or group of strains, that are most common in Asia) and HIV-2 protease
("HIV-2" is the predominant subtype in Africa). "HIV-1b" is the subtype of HIV most commonly found in the U.S. and in Europe. The current anti-AIDS drugs were all
designed and optimized against HIV-1b, but the FightAIDS@Home project is devoted to trying to help all patients with HIV throughout the world.
This experiment involves faah5224 - faah5319.
These calculations began on 03/03/2009 and ended on 3/31/2009.

Experiment 24: 100% Completed

Similar to Experiment 12, this experiment performed by Dr. Ruth Huey involves HIV protease "cross-docking" (i.e., this is a test of the new AutoDock code and the new scoring function that
involves docking all the known HIV protease inhibitors against 100 different crystal structures of HIV protease).
This experiment involved faah4998 - faah5017.
These calculations began 08/11/2008 and finished 08/31/2008.

Experiment 23: 100% Completed

Similar to Experiments 19 and 19a, this Relaxed Complex experiment involves docking the different FDA-approved HIV protease inhibitors (and a few compounds still in development) against the active site of 2,000 different snapshots of HIV-1b protease that were harvested from a Molecular Dynamics simulation.
However, this experiment involves docking these reference compounds against conformations of the V82F/I84V multi-drug resistant "super bug" of HIV protease. We'll compare the performance of these compounds in this experiment versus their calculated affinities from Experiments 19 and 19a.
The reference compounds used in Experiments 19, 19a, and 23 include the FDA-approved drugs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, while the compounds in development include AB2, AB3, JE-2147, KNI-272, TL3, and TMC-126.
This experiment involves faah4726 - faah4791.
These calculations began 12/01/2008, and they finished 02/19/2009.

Experiment 22: 100% Completed

This Relaxed Complex experiment is very similar to Experiment 21, but this time the "DTP" library is being docked against the potential allosteric inhibitor site on the peripheral surface of HIV protease (i.e., the "exo" site), instead of docking them against the active site.
These compounds are also being docked against the same "QR-selected" subset of conformations from the V82F/I84V multi-drug-resistant mutant of HIV protease. For a description of the QR method and a few citations, see the description of Experiment 21.
Experiment 22 involves faah4417 - faah4622 and faah5018 - faah5223.
These calculations began 10/18/2008, and they ended 03/05/2009.

Experiment 21: 100% Completed

This Relaxed Complex experiment is testing both a new library of ligands and a new
method for selecting the snapshots of the target from MD against which to dock these compounds. The first 1/3 of ligands from the NCI's
"DTP" library of compounds is being tested now, while we prepare the files that describe the other 2/3 of this library of compounds.
**Update 07/31/2008** All 3/3 of this library have now been prepared by Dr. Stefano Forli. The other 2/3 of this experiment have been submitted.
These compounds were "moderately active" in cell-based assays at the NCI, but noone knows which targets these bind to or how they are able to
inhibit them. These compounds are being docked against the active site of a "QR-selected" subset of conformations harvested from
Molecular Dynamics simulations of the V82F/I84V multi-drug-resistant mutant of HIV protease (i.e., a target from one of the most drug-resistant
"super bugs" of HIV). The Structure QR method is a new tool for selecting a structurally diverse, non-redundant set of conformations from a
group of different structures that have similar sequences.
We thank John Eargle of the Luthey-Schulten lab at UIUC for helping us learn how to apply this method. For more info. on QR, see P. O'Donoghue and Z. Luthey-Schulten; Evolutionary profiles derived from the QR factorization of multiple structural alignments gives an economy of information; J. Mol. Biol., 346, 875-894, (2005). See also MultiSeq of VMD: Elijah Roberts, John Eargle, Dan Wright, and Zaida Luthey-Schulten; MultiSeq: Unifying sequence and structure data for evolutionary analysis; BMC Bioinformatics, 7:382 (2006).
This experiment involves faah4314 - faah4416, faah4623 - faah4725, and faah4792 - faah4997.
These calculations began 08/28/2008, and they finished 2/19/2009.

Experiment 20: 100% Completed

This Relaxed Complex experiment is similar to Experiment 16, but different run parameters are being used during the docking and several different protocols for preparing the input files of these compounds are being tested (such as using different protocols to calculate the charges on the atoms within each ligand, using different "atom types" to describe the ligands, and using different protocols for minimizing the structures of the ligands).
Thus, this experiment will also allow us to investigate the best way(s) for preparing ligands that will be used in subsequent Relaxed Complex experiments.
This experiment involves faah4202 - faah4313.
These calculations began 06/08/2008, and they ended on 9/30/2008.

Experiment 19a: 100% Completed

This Relaxed Complex experiment involves docking the different FDA-approved HIV protease inhibitors (and a few compounds still in development) against the active site of 2,000 different snapshots of the wild type HIV-1b protease that were harvested from the same Molecular Dynamics simulation discussed above in Exp. 19.
These calculations will provide a base-line against which to compare the performance of the compounds used in Experiment 19. Different protocols for preparing the input files of these current drugs were used
(such as using different protocols to calculate the charges on the atoms within each ligand, using different "atom types" to describe the ligands, and using different protocols for minimizing the structures of the ligands).
Thus, this experiment will also allow us to investigate the best way(s) for preparing ligands that will be used in subsequent Relaxed Complex
experiments. The reference compounds used in Experiment 19a include the FDA-approved drugs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, while the compounds in development include AB2, AB3, JE-2147, KNI-272, TL3, and TMC-126.
This experiment involved faah4070 - faah4201.
These calculations began 05/26/2008 and finished 08/19/2008.

Experiment 19: 100% Completed

This experiment is similar to Exp. 13, but different run parameters are being used (for example, 2 point cross-over is being used, while Exp. 13 used the arithmetic crossover protocol in the genetic algorithm used in the docking calculations; a new and improved version of the AutoDock code is being used, as well). Exp. 19 is a Relaxed Complex experiment of the "9 false negatives" from the NCI Diversity Set. These 9 compounds did not dock well in previous experiments (by Max Chang and Dr. Lindy Lindstrom) that targeted different crystal structures of HIV protease, but they did display some activity in an experimental assay against HIV protease. Different versions of these 9 ligands and of a few reference compounds are being docked against the active site in 2,000 different snapshots of the wild type protease that were harvested from Dr. Alex Perryman's previously-published Molecular Dynamics simulations (i.e., the cover article of the April, 2004, issue of Protein Science).
The reference compounds used in Experiment 19 include the FDA-approved drugs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, while the compounds in development include AB2, AB3, JE-2147, KNI-272, TL3, and TMC-126.
To view some of the recent results from the Relaxed Complex experiments on these reference compounds, see the graph with part of Indinavir's Relaxed Complex "trajectory" or the comparison of AB2's versus AB3's RC "trajectories" at the bottom of this page.
This experiment involved faah4000 - faah4069.
These calculations began 05/02/2008 and finished 06/14/2008.

Results of these FightAIDS@Home experiments
are available to the public as raw, unprocessed AutoDock dlg files upon request.
E-mail Dr. Daniel N. Santiago = dsantiag ]~[ scripps . edu (use the @ symbol to replace the ]~[ and remove the spaces) for further information. Please
include the phrase "FAAH data" in the subject line of your e-mail.
Since the amount of data is on the order of many terabytes, you will need to provide
suitable media (such as external hard drives) for receiving a copy of these results.